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A randomized placebo-controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (National Cancer Institute of Canada—Clinical Trials Group Trial, MA.12)
original article
Annals of Oncology 21: 283–290, 2010 doi:10.1093/annonc/mdp326 Published online 23 July 2009
A randomized placebo-controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (National Cancer Institute of Canada—Clinical Trials Group Trial, MA.12) V. H. C. Bramwell1*, K. I. Pritchard2, D. Tu3, K. Tonkin4, H. Vachhrajani5, T. A. Vandenberg6, J. Robert7, A. Arnold8, S. E. O’Reilly9, B. Graham3 & L. Shepherd3 1
Background: In the early 1990s, the role of adjuvant tamoxifen in premenopausal women with early breast cancer (EBC) was not established. Similarly, optimum timing relative to adjuvant chemotherapy and efficacy of tamoxifen in hormone receptor-negative tumors were unclear. Patients and methods: Premenopausal women with EBC, any hormone receptor status, after surgery received standard adjuvant chemotherapy [doxorubicin (adriamycin)/cyclophosphamide, cyclophosphamide/methotrexate/5fluorouracil, or cyclophosphamide/epirubicin/5-fluorouracil] followed by randomization to tamoxifen or placebo for 5 years. Outcomes were overall survival (OS), disease-free survival (DFS), toxicity, and compliance with therapy. Results: Median follow-up for 672 women was 9.7 years. Multivariate analysis showed improved DFS [78.2% versus 71.3% at 5 years; hazard ratio (HR) 0.77; P = 0.056] and a trend for improved OS (86.6% versus 82.1% at 5 years; HR 0.78; P = 0.12). There was no evidence of greater benefit for the receptor-positive subgroup. Compliance with treatment was suboptimal in both arms, with 103 (31%) women on tamoxifen and 70 (21%) on placebo-stopping therapy early because of toxicity, refusal, or other choices. Conclusions: Adjuvant tamoxifen, given after chemotherapy to premenopausal women with EBC, improved 5-year DFS. Poor compliance may have reduced treatment efficacy. Key words: early breast cancer, premenopausal, tamoxifen following chemotherapy
introduction In 1992, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) published the 1990 meta-analysis of 75 000 women in randomized trials evaluating systemic adjuvant therapies for early breast cancer (EBC) [1]. This established the benefits of polychemotherapy alone, and tamoxifen alone, in reducing recurrence and improving survival. However, the meta-analysis indicated little advantage for tamoxifen added to polychemotherapy [6362 women—risk reduction (RR) recurrence 7%, RR mortality 3%] in women <50 years. This meta-analysis [1] also established 5 years of tamoxifen as an optimum duration, but its role in women with estrogen receptor (ER)-negative tumors remained unresolved.
*Correspondence to: Dr V. H. C. Bramwell, Department of Medical Oncology, Tom Baker Cancer Centre, 1331-29th Street North West, Calgary, Alberta T2N 4N2, Canada. Tel: +1-403-521-3707; Fax: +1-403-238-1651; E-mail: [email protected]
Superiority of sequential rather than concurrent use of tamoxifen with chemotherapy was not confirmed until publication of Intergroup 0100 study results in 2002 [2]. However, a theoretical concern [3], together with experimental data [4], indicating that tamoxifen given concurrently with chemotherapy could decrease rates of cell division reducing susceptibility to cell cycle active chemotherapy agents, provided the basis for sequential use of tamoxifen in several adjuvant chemohormonal trials started in the 1990s. The interaction of chemotherapy and tamoxifen may be quite complex in premenopausal women. Chemotherapy-induced amenorrhea is often associated with better outcomes, although controversy remains [5]. In 1992, there was substantial uncertainty as to whether tamoxifen administered with or after chemotherapy in premenopausal women was redundant or conferred benefit similar to that seen in postmenopausal women. Thus, in 1992, the National Cancer Institute of Canada—Clinical Trials Group (NCIC CTG) Breast Committee initiated Mammary (MA).12 in premenopausal women with
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Received 19 March 2009; revised 5 May 2009; accepted 6 May 2009
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Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, Alberta; 2Department of Medical Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario; Central Office, National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario; 4Department of Medical Oncology, Cross Cancer Institute, Edmonton, Alberta; 5Department of Radiation Oncology, Saskatoon Cancer Centre, Saskatoon, Saskatchewan; 6Department of Medical Oncology, London Regional Cancer Program, London, Ontario; 7Department of Surgical Oncology, Hoˆpital Du Saint-Sacrement, Quebec City, Quebec; 8Department of Medical Oncology, Juravinski Cancer Centre, Hamilton, Ontario and 9Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada 3
original article
Annals of Oncology
node-positive breast cancer, evaluating the benefit of 5 years of adjuvant tamoxifen versus placebo following completion of adjuvant chemotherapy. Participants could opt for one of three well-established chemotherapy regimens, cyclophosphamide/ methotrexate/5-fluorouracil (CMF), cyclophosphamide/ epirubicin/5-fluorouracil (CEF) as used in an NCIC CTG trial that had just been completed [6], or doxorubicin (adriamycin)/ cyclophosphamide (AC) [7].
known to be alive. Disease-free survival (DFS), the secondary efficacy end point, was calculated from randomization to the earliest date of recurrence or death or censored on the last date the patient was known to be alive. Contralateral breast cancer was considered a second primary malignancy. The worse grade of adverse event/toxicity according to the NCIC CTG Expanded Common Toxicity Criteria was recorded for each patient at randomization (baseline), during therapy with tamoxifen/placebo (acute) and after completion of therapy (not reported, except second malignancies).
patients and methods
statistical analysis
patient population
treatment plan The study was approved by local Research Ethics Boards, and patients provided written informed consent. Staging investigations included history, physical examination, complete blood count and liver function tests before chemotherapy, and chest radiograph and bone scan within 8 weeks of starting chemotherapy. Patients were required to start chemotherapy within 14 weeks of first histological diagnosis of breast cancer and to complete a course of standard adjuvant chemotherapy with six cycles of CMF or CEF [6] or four cycles of AC [7]. After stratification for type of chemotherapy (CMF versus CEF versus AC), hormone receptor status (ER and/or PgR positive versus ER and PgR negative), and nodal status (0 versus 1–3 versus 4–9 versus 10+), through the central office of NCIC CTG, women were randomized to tamoxifen/placebo on/after day 8 of cycle 6 of CMF/CEF or day 1 of cycle 4 of AC and were required to start study medication within 42 days of completing i.v. chemotherapy. Tamoxifen/placebo was provided by AstraZeneca, Missisauga, Ontario, as 20 mg tablets to be taken daily for 5 years.
follow-up After starting tamoxifen/placebo, women were seen every 3 months for 2 years, every 6 months for 3 years, and then yearly. Adverse events/toxic effects of tamoxifen/placebo were recorded. When patients stopped blinded treatments, reasons were documented, including treatment completion, recurrence, death, intercurrent illness, toxicity of treatment, refusal (for reasons other than toxicity), major protocol violation (started another hormonal therapy before progression), and others. Other hormonal therapies (including nonstudy tamoxifen) taken before progression (during or after off-protocol treatment) were also recorded.
outcome measures The primary end point was overall survival (OS), calculated from date of randomization to date of death or censored on the last day the patient was
284 | Bramwell et al.
results patient population From 1993 to 2000, 672 women were randomized: 338 to tamoxifen and 334 to placebo. Median age was 46 years (range 29–58). Other characteristics are summarized in Table 1. ER assays were done by the biochemical method in 202 (60%) of women randomized to tamoxifen and 172 (51%) on placebo. The remaining ER assays were done by immunohistochemistry (one patient on each arm had both assays). All PgR assays were done by biochemistry. Hormone receptor status was positive (ER positive and/or PgR positive) in 505 (75%) women. Eighteen patients did not meet the eligibility criteria (Appendix, Figure A1). On tamoxifen, these included one incomplete resection, six incomplete screening tests, three inappropriate chemotherapy regimens, and three not meeting high-risk criteria for node-negative disease. On placebo, five patients had incomplete screening tests. All randomized patients were included in survival analyses on an intention-to-treat basis. outcomes—OS and DFS At data cut-off for this analysis, March 2007, median follow-up was 9.7 years (range 0.2–13.1 years), and 169 women had died, 77 (23%) on tamoxifen and 92 (27.5%) on placebo (Table 2). The Kaplan–Meier curves for OS (Figure 1A) show 5-year OS
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Women with histologically confirmed breast cancer who had undergone complete or segmental mastectomy plus axillary node dissection were included. Pre-/perimenopausal status was characterized by one of the following: normal menstruation, amenorrhea <1 year, biochemical evidence of ovarian function, amenorrhea for 1–3 years in women <52 years, or hysterectomy without oophorectomy in women <56 years [criteria of the International Breast Cancer Study Group (IBCSG)]. Patients with pathological T1–4, N0–2, and M0 tumors were eligible. Initially, entry was restricted to women with node-positive disease but, from February 1995, women with high-risk node-negative tumors (tumor ‡1 cm and high histological grade or lymphovascular invasion or both) were included. Determination of levels of at least one hormone receptor [ER and/or progesterone receptor (PgR)], by biochemical (positive ‡10 fmol/mg protein) or immunohistochemical assay (as determined by the local pathologist), was required but patients with any receptor status were eligible. Patients were excluded if they had distant metastases, residual disease in the breast or axilla, other serious medical illnesses, or a previous cancer. Women considering pregnancy or using hormones were excluded. Brief exposure to tamoxifen (£2 weeks) was permitted.
The trial was designed to detect, with 80% power and a two-sided alpha of 5%, an increase in 5-year OS from 70% for women on placebo to 78% for those receiving tamoxifen [corresponding to a hazard ratio (HR) of 0.69]. This would require 242 deaths at final analysis. It was projected that this number of events would be observed by enrolling 800 patients over 5 years and following them for five additional years. The trial was activated in July 1993. Based on the recommendation of the Data Safety and Monitoring Committee (DSMC), the trial closed in April 2000 after 672 patients were randomized since, because of slow accrual, it was projected that 242 deaths would still be observed with 5 years’ additional follow-up. Two interim analyses were scheduled when one-third (80) and twothirds (160) of deaths required were observed. The DSMC recommended continuation after the first interim analysis. After reviewing results of the second interim analysis and a supplemental futility analysis, the DSMC accepted a proposal by the Trial Committee to publish these results. OS and DFS of the two treatment groups were described by Kaplan– Meier curves and compared by a log-rank test adjusting stratification factors at randomization. The Cox proportional hazards model was used to adjust the observed treatment effect for the three stratification factors and four other potential prognostic factors: age (£45 versus >45 years); Eastern Cooperative Oncology Group performance status (0 versus 1, 2); time from initial pathological diagnosis to randomization (£6 versus >6 months); and pathological T stage (£2 versus >2 cm). The chi-square test was used to compare rates of adverse events/toxicity between treatment groups. All statistical tests were two sided.
original article
Annals of Oncology
For DFS, there were 226 recurrences or deaths without recurrence, 105 (31%) on tamoxifen and 121 (36%) on placebo (Table 2). The Kaplan–Meier curves for DFS (Figure 1B) show 5year DFS rates of 78.2% on tamoxifen and 71.3% on placebo. The HR from the stratified Cox proportional hazards model was 0.77 (95% CI 0.59–1.01; P = 0.056). Table 3 shows that as for OS, there was no evidence for a greater effect of tamoxifen on DFS in the hormone receptor-positive or ER-positive subgroups (P values of interaction tests 0.87 and 0.26, respectively).
Table 1. Patient characteristics according to treatment arms
protocol treatment Ten patients on tamoxifen and seven on placebo never started protocol treatment. Among them, one on tamoxifen and zero on placebo were ineligible. All patients were off-protocol treatment at time of data cut-off. Of women starting treatment, 103 (31%) on tamoxifen and 70 (21%) on placebo stopped early because of toxicity, refusal, protocol violation, and other causes (Table 4). Overall, 29% on tamoxifen and 27% on placebo received £2 years of protocol treatment. Forty-one (12.5%) on tamoxifen and 32 (10%) on placebo received other hormones before recurrence, which included progestogens for menopausal symptoms, tamoxifen extended beyond 5 years, and aromatase inhibitors (Table 4). Among them, 17 on tamoxifen and 22 on placebo started off-label tamoxifen before the scheduled end of blinded treatment.
Characteristic Receptor status ER and/or PgR positive ER and PgR negative ER negative and PgR unknown ER positive ER negative PgR positive PgR negative PgR unknown Nodal status Node negative 1–3 nodes 4–9 nodes 10+ nodes Adjuvant chemotherapy CEF CMF AC Age £29 30–39 40–49 ‡50 Stage (pathological) I II III Pathological T stage 1 2 3/4 ECOG status 0 1 2 Menstrual status (at randomization) Regular menses Irregular menses No menses >3 months Previous hysterectomy No data
Tamoxifen n %
Placebo n %
Total N %
252 50 36
74 15 11
253 26 55
76 8 16
505 75 76 11 91 14
223 115 132 60 146
66 34 39 18 43
231 103 119 41 174
69 31 36 12 52
454 218 251 101 320
84 190 55 9
25 56 16 3
83 187 53 11
25 56 16 3
167 25 377 56 108 16 20 3
73 153 112
22 45 33
73 151 110
22 45 33
146 22 304 45 222 33
68 32 37 15 48
1 64 210 63
0 19 62 19
2 66 210 56
0 20 63 17
3 0 130 19 420 63 119 18
33 284 21
10 84 6
37 278 19
11 83 6
70 10 562 84 40 6
140 179 19
41 53 6
149 165 20
45 49 6
289 43 344 51 39 6
234 100 4
69 30 1
206 125 3
62 37 1
440 65 225 34 7 1
85 36 129 17 71
25 11 38 5 21
93 39 121 20 61
28 12 36 6 18
178 75 250 37 132
ER, estrogen receptor; PgR, progesterone receptor; CEF, cyclophosphamide/epirubicin/fluorouracil; CMF, cyclophosphamide/ methotrexate/5-fluorouracil; AC, doxorubicin(adriamycin)/ cyclophosphamide; ECOG, Eastern Cooperative Oncology Group.
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26 11 37 6 20
adverse events/toxicity Toxicity was evaluated in 328 patients on tamoxifen and 327 on placebo who started protocol treatment (Appendix, Figure A1). Table 2. Outcome events—deaths and recurrences by treatment arm Tamoxifen n Patients OS—total deaths Breast cancer Other malignancy Othera DFS—total events Recurrences Locoregional only Breast Chest wall Regional nodes Distant only Multiple sites Boneb Liver Lung Brain Ascites/effusions Other Death without recurrence
338 77 72 2 3 105 101 17 11 2 4 51 33 59 45 40 24 38 30 4
% 23
31 30 5
15 10
1
Placebo n 334 92 86 4 2 121 116 14 10 1 3 57 45 69 54 53 27 47 34 5
% 28
36 35 4
17 13
1
a
Tamoxifen: nonprotocol treatment complication (1), intracranial bleed (1), unknown, but extensive metastases (1); placebo: motor vehicle accident (1), suspected suicide (1). b Single patient can have multiple sites of recurrence. OS, overall survival; DFS, disease-free survival.
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rates of 86.6% on tamoxifen and 82.1% on placebo. The HR from the stratified Cox proportional hazards model was 0.78 [95% confidence interval (CI) 0.57–1.06; P = 0.12]. The effect of tamoxifen was explored in subgroups defined by overall hormone receptor and ER receptor-only status (Table 3). There was no evidence of greater efficacy for tamoxifen in the hormone receptor-positive or ER receptor-positive subgroups (P values of interaction tests 0.71 and 0.14, respectively).
original article
Annals of Oncology
discussion
Figure 1. (A) Kaplan–Meier curves for overall survival, tamoxifen versus placebo; (B) Kaplan–Meier curves for disease-free survival, tamoxifen versus placebo.
In this placebo-controlled study, adjuvant tamoxifen following chemotherapy produced improved DFS (HR 0.77; P = 0.056) and a trend for improved OS (HR 0.78; P = 0.12) in premenopausal women with EBC. Although exploratory subgroup analysis indicated a trend for greater benefit in women with ER-negative tumors, this was not statistically significant. Such a finding has no biological rationale and is not in agreement with results of other similar studies [8–10]. A number of factors delayed analysis of this trial to a time when use of adjuvant tamoxifen has become standard practice after adjuvant chemotherapy in premenopausal women with receptor-positive tumors. In the late 1990s, slow accrual probably reflected an increasing conviction among physicians and patients that tamoxifen was beneficial in this setting, despite limited data actually available at that time [11]. The study was closed with a reduced sample size because of slow
Table 3. Effect of tamoxifen on OS and DFS according to hormone receptor subgroups Tamoxifen Total patients OS Receptor status ER and/or PgR positive ER and PgR negative ER negative, PgR unknown ER status Positive Negative DFS Receptor status ER and/or PgR positive ER and PgR negative ER negative, PgR unknown ER status Positive Negative
% Surviving 5 years
Placebo Total patients
% Surviving 5 years
HR (95% CI)
252 50 36
90 76 78
253 26 55
85 73 72
0.83 (0.58–1.18) 0.78 (0.34–1.81) 0.67 (0.29–1.56)
223 115
90 81
231 103
86 72
0.94 (0.65–1.38) 0.61 (0.37–1.01)
251 50 36
80 70 78
253 26 55
73 69 65
0.82 (0.61–1.11) 0.83 (0.38–1.82) 0.65 (0.30–1.43)
222 115
79 77
231 103
75 64
0.90 (0.66–1.24) 0.65 (0.41–1.03)
OS, overall survival; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; PgR, progesterone receptor.
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At baseline, 54% and 50% of women subsequently randomized to tamoxifen and placebo, respectively, were complaining of hot flashes. Similar numbers in each arm, 129 (38%) on tamoxifen and 121 (36%) on placebo, had ceased menstruation for at least 3 months, and a further 36 (11%) on tamoxifen and 39 (12%) on placebo were having irregular periods (Table 1). Large numbers of grade 1/2 acute toxic effects were reported but were similarly distributed across the arms. For grade 3/4 (Appendix, Table A1) toxic effects, the only important difference was in frequency of severe hot flashes, which were significantly worse on tamoxifen (tamoxifen 23% versus placebo 14%; P = 0.005). Twenty-one (6%) patients on tamoxifen and 33 (10%) on placebo developed 56 second malignancies. There were fewer contralateral breast cancers (14 versus 18) and fewer other malignancies (7 versus 17; P = 0.07) in the tamoxifen arm. The only two cases of endometrial cancer were on placebo.
original article
Annals of Oncology
Table 4. Compliance with study medication Placebo n
%
338
100
334
100
175 50 1 9 29 44 13 17 328
52 15 0 3 8 13 4 5 100
174 78 1 11 15 35 12 8 327
52 23 0 3 5 11 4 2 100
64 33 19 23 189 7
19 10 6 7 58 2
45 41 31 21 189 2
14 13 9 6 58 1
10
2 0 0 30
9
0 1 6 34
17 12 1 0 4
20 1 0 3 2
0 11 1
5 2 0
a
Included development of contralateral breast cancer. Ineligible, noncompliant, stopped early/unblinded in error, physician advice, desire for pregnancy, left the country. c A patient may have received more than one hormonal agent. b
accrual after recruitment of 672 women (planned accrual 800) based on recalculation of the statistical assumptions, as outlined in the ‘Patients and Methods’ section. Our primary end point was OS, but over the time span of the trial, mortality was much lower than anticipated, probably because of increasing efficacy of adjuvant therapies and better salvage therapies for metastatic disease. The recent declining mortality for women with EBC has been well documented across many countries [12]. Several studies of similar design (evaluating tamoxifen given after adjuvant chemotherapy in premenopausal women with EBC) have demonstrated improvements in DFS, but are not
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Total off treatment Reasons Treatment completed Recurrence/progression Death Intercurrent illnessa Toxicity treatment Refusal Protocol violation Otherb Number treated patients Duration of study medication (months) 0–12 13–24 25–36 37–48 49–60 Other hormones before progression and during protocol treatmentc Tamoxifen Letrozole Progestogen Other hormones before progression and after protocol treatmentc Not completed 5 years of blinded treatment Tamoxifen Letrozole Anastrozole Exemestane Progestogen Completed 5 years of blinded treatment Tamoxifen Letrozole Exemestane
Tamoxifen n %
definitive with respect to OS [8–10]. Our study is the remaining unpublished randomized trial directly addressing this question. A future individual patient data meta-analysis may be more informative concerning the effects of tamoxifen on OS in this population. The study most comparable to ours was conducted by the IBCSG (13.93), 1993–1999, and recruited premenopausal nodepositive women [8]. All received chemotherapy followed by randomization to tamoxifen for 5 years or no endocrine therapy. Of 1246 assessable patients, 735 (59%) had ER-positive tumors, and patients receiving tamoxifen versus control had improved DFS at 5 years (75% versus 62%; HR 0.59; P = 0.0001), although no benefit was seen in the ER-negative cohort. There were no significant differences in OS in ER-positive (HR 0.86; P = 0.36) or ER-negative subgroups (HR 0.92; P = 0.63). Intergroup protocol INT-0102 [9], 1989–1993, compared 5 years of tamoxifen with no endocrine therapy in 1690 women with high-risk node-negative breast cancer (56% premenopausal) who had completed adjuvant chemotherapy. At 10 years, improved DFS (HR 1.32; P = 0.003) and OS (HR 1.26; P = 0.03) were seen in the ER-positive subgroup, but not overall. Subgroup analysis was not carried out according to menopausal status. In European Organisation for Research and Treatment of Cancer (EORTC) study 10901 [10], 1863 women recruited 1991–1999, after chemotherapy, were randomized between tamoxifen 20–30 mg daily for 3 years or no endocrine therapy. Analysis was based on 1724 patients, 73% of whom were pre-/ perimenopausal. Five-year DFS figures were 67% versus 63%, favoring tamoxifen (HR 0.84; P = 0.035). Benefit was greater in the ER-positive subgroup, but menopausal status did not influence effects of treatment. In a North American setting, adjuvant chemotherapy remains the standard of care for premenopausal women with high-risk node-negative or node-positive EBC. For women with endocrine-responsive (hormone receptor positive) tumors, chemotherapy is usually followed by 5 years of tamoxifen. However, several European studies have shown that ovarian function suppression with or without tamoxifen can be as effective as standard CMF chemotherapy [13–15]. IBCSG is leading an international collaboration exploring ovarian function suppression with or without adjuvant chemotherapy in premenopausal women with EBC, through two ongoing randomized trials (IBCSG 24.02 Suppression of Ovarian Function, IBCSG 25.02 Tamoxifen and Exemestane Trial) [16]. The placebo-controlled design of our study allowed us to collect detailed comparative data on compliance, and we found that 31% on tamoxifen and 21% on placebo-stopped study medication prematurely for reasons other than recurrence, death, or intercurrent illness. The greatest attrition occurred in the first 24 months. Although data from EBCTCG [1, 17] showed benefit for durations of adjuvant tamoxifen as short as 1 year, results were better with longer therapy and currently, at least 5 years of therapy is regarded as optimal. We know that 17 stopping tamoxifen and 22 stopping placebo went on to receive open-label tamoxifen, but this may be an underestimate given its wide availability. As few patients received aromatase inhibitors, it is unlikely that their use affected efficacy outcomes.
original article
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To date, second malignancy rates are low and do not differ significantly between the arms. The only two cases of endometrial cancer occurred on placebo, and it is probable that women entering the menopause are less susceptible to the carcinogenic effects of tamoxifen on the endometrium [29]. A delayed effect is still possible, although all women have been off therapy for 1–8 years. In conclusion, in MA.12, DFS at 5 years was marginally improved for premenopausal women receiving 5 years of tamoxifen after adjuvant chemotherapy for EBC. However, poor compliance with therapy is likely to have influenced the efficacy of treatment in this trial and other similar studies. Some of the compliance issues clearly related to the physical and emotional consequences of early menopause induced by adjuvant chemotherapy, but there were other contributory factors (Table 4). These findings have implications for the use of oral anticancer medications in many settings [30].
funding AstraZeneca, through the National Cancer Institute of Canada Clinical Trials Group; Canadian Cancer Society, through the National Cancer Institute of Canada (# 4448).
acknowledgement This paper was presented at American Society Clinical Oncology meeting 2007 and San Antonio Breast Cancer Symposium 2007.
references 1. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31 000 recurrences and 24 000 deaths among 75 000 women. Lancet 1992; 339: 71–85. 2. Albain KS, Green SJ, Ravdin PM et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 2002; 21: 37a (Abstr 143). 3. Osborne CK. Effects of estrogens and antiestrogens on cell proliferation: implications for the treatment of breast cancer. Cancer Treat Res 1988; 39: 111–129. 4. Goldenberg GJ, Froese EK. Antagonism of the cytocidal activity and uptake of melphalan by tamoxifen in human breast cancer cells in vitro. Biochem Pharmacol 1985; 34: 763–770. 5. Walshe JM, Neelima D, Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 2006; 24: 5769–5779. 6. Levine MN, Bramwell VH, Pritchard KI et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil in premenopausal women with node positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1998; 16: 2651–2658. 7. Fisher B, Anderson S, Tan-Chiu E et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 2001; 19: 931–942. 8. International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 2006; 24: 1332–1341. 9. Hutchins LF, Green SJ, Ravdin PM et al. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil with and without tamoxifen for
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The influence of compliance issues on the main efficacy outcomes will have been complex although a dilution of the potential beneficial effects of tamoxifen seems likely. None of the other comparable studies was placebo controlled, and data on other hormonal therapies used by women in control arms were not reported [8–10]. In INT-0102 [9], 57% of women completed ‡4.5 years of tamoxifen, with 8% stopping due to toxicity and 7% refusing therapy. In IBCSG-93 [8], 8% of women did not start tamoxifen and 33% discontinued drug prematurely. In EORTC 10901 [10], 4.4% stopped tamoxifen due to toxicity. In this study, a shorter planned duration of tamoxifen (3 years) may account for the lower dropout rate, but methodology for documenting compliance was not reported. Early discontinuation of hormonal therapy has also been reported in aromatase inhibitor studies. In ATAC, 22%–26% across the three arms withdrew from therapy [18]. A lower proportion of patients in Intergroup Exemestane Study, 13%–15%, discontinued therapy prematurely after a median of 36 months [19]. In MA.17, 19%–20% of women discontinued treatment early [20]. Compliance data were not reported for BIG 1–98 [21]. In a practice setting, problems with adherence to aromatase inhibitor therapy have also been documented [22]. Poor compliance with adjuvant tamoxifen has been described in clinical practice. Partridge et al. [23], documenting filled prescriptions for adjuvant tamoxifen among 2378 women through New Jersey’s Pharmaceutical prescription program, found that 23% of patients missed taking tamoxifen on >20% of days studied, although 87% filled prescriptions in the first year. Overall adherence was 50% by year 4. Also using prescription refill data from a national prescribing database, Barron et al. [24] found that 22% of 2816 women stopped tamoxifen within 1 year, increasing to 35% at 3.5 years. Data from another community-based study of 2080 women demonstrated a correlation between poor adherence to adjuvant tamoxifen and increased risk of death from breast cancer [25]. The gaps between evidence-based recommendations for adjuvant hormonal therapy and clinical practice were the subject of a recent editorial [26]. Genetic variation in cytochrome P-450 2D6 affecting metabolism of tamoxifen may account for different degrees of toxicity and thus compliance [27]. In MA.12, amenorrhea rates were close to 50% after chemotherapy before randomization to tamoxifen/placebo, but were similar between the arms, and this is unlikely to have influenced the efficacy of treatment. Many ‘toxic effects’ recorded in our study, for both tamoxifen and placebo, probably were related to chemotherapy-induced menopause [28] and/or prolonged chemotherapy-related side-effects, particularly in the first year. This may account for higher dropout rates in studies including high proportions of premenopausal women treated with adjuvant chemotherapy, compared with aromatase inhibitor trials in which all women were postmenopausal, regardless of whether they received chemotherapy. Toxic effects clearly worse on tamoxifen included vaginal discharge/fibrosis and hot flashes, as documented in other studies. Our finding that mood changes were more frequent on placebo indicates that these are not specific side-effects of tamoxifen, but have other causes such as premature menopause, the emotional toll of the disease, and effects of multiple treatments.
Annals of Oncology
original article
Annals of Oncology
high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 2005; 23: 8313–8321. 10. Morales L, Canney P, Dyczka J et al. Postoperative adjuvant chemotherapy followed by adjuvant tamoxifen versus nil for patients with operable breast cancer: a randomized phase III trial of the European Organisation for Research and Treatment of Cancer Breast Group. Eur J Cancer 2007; 43: 331–340. 11. Bramwell VHC, Pritchard KI. Tamoxifen added to adjuvant chemotherapy in premenopausal women with early breast cancer: is it standard practice or still a subject for study? Eur J Cancer 1999; 35: 1625–1627. 12. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005; 365: 1687–1717.
14. Jonat W, Kaufmann M, Sauerbrei W et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002; 20: 4628–4635. 15. Jakesz R, Hausmaninger H, Kubista E et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002; 20: 4621–4627. 16. Regan MM, Pagani O, Walley B et al. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy? Ann Oncol 2008; 19: 1213–1215.
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28.
29.
17. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351: 1451–1467. 18. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for
30.
appendix
Figure A1. Consort diagram.
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13. Boccardo F, Rubagotti A, Amoroso D et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. J Clin Oncol 2000; 18: 2718–2727.
19.
adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 2002; 359: 2131–2139. Coombes RC, Hall E, Gibson LJ et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women wit primary breast cancer. N Engl J Med 2004; 350: 1081–1092. Goss PE, Ingle JN, Martino S et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005; 97: 1262–1271. The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2747–2757. Partridge AH, LaFountain A, Mayer E et al. Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol 2008; 26: 556–562. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 2003; 15: 602–606. Barron TI, Connolly RM, Bennett K et al. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer 2007; 109: 832–839. McCowan D, Shearer J, Donnan PT et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008; 99: 1763–1768. Kahn KL. Moving research from bench to bedside to community: there is still more to do. J Clin Oncol 2008; 26: 523–526. Rae JM, Sikora MJ, Henry NL et al. Cytochrome p450 2D6 activity predicts adherence to tamoxifen therapy. Breast Cancer Res Treat 2007; 106: S21 (Abstr 77). Tchen N, Juffs HG, Downie FP et al. Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol 2003; 21: 4175–4183. Fisher B, Costantino JP, Redmond CK et al. Endometrial cancer in tamoxifentreated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86: 527–537. Partridge AH. Non-adherence to endocrine therapy for breast cancer. Ann Oncol 2006; 17: 183–184.
original article
Annals of Oncology
Table A1. Numbers of acute adverse events/toxic effects (>10% incidence either arm) Adverse event
4
Total (%)
%R
Placebo (327 patients) 1 2 3
4
Total (%)
%R
82 69 79
30 10 3
3 5 0
0 3 0
115 (35) 87 (27) 82 (25)
0 0 0
74 44 45
20 14 2
1 6 0
0 0 0
95 (29) 64 (20) 47 (14)
1 0 0
44
11
0
0
55 (17)
6
61
9
0
0
70 (21)
7
16 61
205 134
0 75
0 0
221 (67) 270 (82)
34 78
26 87
198 131
0 47
0 0
224 (69) 265 (81)
37 75
60 125 40
13 24 13
4 1 3
0 0 0
77 (23) 150 (46) 56 (17)
4 19 4
59 136 43
33 27 17
4 3 3
0 0 0
96 (29) 166 (51) 63 (19)
4 23 2
45 21
8 6
1 0
0 0
54 (16) 27 (8)
7 1
46 29
8 9
1 3
0 0
55 (17) 41 (13)
8 2
66
22
0
0
88 (27)
21
55
9
2
0
66 (20)
15
28 44
1 8
0 2
0 0
29 (9) 54 (16)
0 1
90 32
2 4
0 1
0 0
92 (28) 37 (11)
0 0
11
13
1
0
25 (8)
1
16
17
0
0
33 (10)
1
15 20 60 39 37
20 11 40 11 5
3 0 6 3 0
0 0 0 0 0
(12) (9) (32) (16) (13)
4 3 17 2 2
27 24 80 55 48
20 13 46 16 4
1 3 7 1 1
0 0 1 0 0
20
11
2
0
33 (10)
1
29
15
3
22
3
0
0
25 (8)
0
22
8
17 14 32
6 1 11
2 0 1
0 0 0
25 (8) 15 (5) 44 (13)
1 1 3
33 29 31
10 3 14
38 31 106 53 42
48 40 134 72 53
(15) (12) (41) (22) (16)
4 4 21 2 2
0
47 (14)
3
2
0
32 (10)
0
0 0 1
0 0 0
43 (13) 32 (10) 46 (14)
2 1 3
%R = considered by investigator to be ‘possibly’, ‘probably’, or ‘definitely’ related to protocol treatment. WBC, white blood cell; Hb, hemoglobin; ALP, alkaline phosphatase; AST, aspartate aminotransferase.
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Blood WBC Neutrophils Hb Cardiovascular Edema Endocrine Amenorrhea Hot flashes Influenza-like symptoms Arthralgia Lethargy Myalgia Gastrointestinal Nausea Abdominal pain Genitourinary Vaginitis/fibrosis Hepatic ALP AST Infection Infection Neurological Headache Insomnia Mood Pain Sensory Osseous Bone pain Pulmonary Cough Skin Alopecia Skin changes Rash/itch
Tamoxifen (328 patients) 1 2 3
Annals of Oncology 21: 283–290, 2010 doi:10.1093/annonc/mdp326 Published online 23 July 2009
A randomized placebo-controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (National Cancer Institute of Canada—Clinical Trials Group Trial, MA.12) V. H. C. Bramwell1*, K. I. Pritchard2, D. Tu3, K. Tonkin4, H. Vachhrajani5, T. A. Vandenberg6, J. Robert7, A. Arnold8, S. E. O’Reilly9, B. Graham3 & L. Shepherd3 1
Background: In the early 1990s, the role of adjuvant tamoxifen in premenopausal women with early breast cancer (EBC) was not established. Similarly, optimum timing relative to adjuvant chemotherapy and efficacy of tamoxifen in hormone receptor-negative tumors were unclear. Patients and methods: Premenopausal women with EBC, any hormone receptor status, after surgery received standard adjuvant chemotherapy [doxorubicin (adriamycin)/cyclophosphamide, cyclophosphamide/methotrexate/5fluorouracil, or cyclophosphamide/epirubicin/5-fluorouracil] followed by randomization to tamoxifen or placebo for 5 years. Outcomes were overall survival (OS), disease-free survival (DFS), toxicity, and compliance with therapy. Results: Median follow-up for 672 women was 9.7 years. Multivariate analysis showed improved DFS [78.2% versus 71.3% at 5 years; hazard ratio (HR) 0.77; P = 0.056] and a trend for improved OS (86.6% versus 82.1% at 5 years; HR 0.78; P = 0.12). There was no evidence of greater benefit for the receptor-positive subgroup. Compliance with treatment was suboptimal in both arms, with 103 (31%) women on tamoxifen and 70 (21%) on placebo-stopping therapy early because of toxicity, refusal, or other choices. Conclusions: Adjuvant tamoxifen, given after chemotherapy to premenopausal women with EBC, improved 5-year DFS. Poor compliance may have reduced treatment efficacy. Key words: early breast cancer, premenopausal, tamoxifen following chemotherapy
introduction In 1992, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) published the 1990 meta-analysis of 75 000 women in randomized trials evaluating systemic adjuvant therapies for early breast cancer (EBC) [1]. This established the benefits of polychemotherapy alone, and tamoxifen alone, in reducing recurrence and improving survival. However, the meta-analysis indicated little advantage for tamoxifen added to polychemotherapy [6362 women—risk reduction (RR) recurrence 7%, RR mortality 3%] in women <50 years. This meta-analysis [1] also established 5 years of tamoxifen as an optimum duration, but its role in women with estrogen receptor (ER)-negative tumors remained unresolved.
*Correspondence to: Dr V. H. C. Bramwell, Department of Medical Oncology, Tom Baker Cancer Centre, 1331-29th Street North West, Calgary, Alberta T2N 4N2, Canada. Tel: +1-403-521-3707; Fax: +1-403-238-1651; E-mail: [email protected]
Superiority of sequential rather than concurrent use of tamoxifen with chemotherapy was not confirmed until publication of Intergroup 0100 study results in 2002 [2]. However, a theoretical concern [3], together with experimental data [4], indicating that tamoxifen given concurrently with chemotherapy could decrease rates of cell division reducing susceptibility to cell cycle active chemotherapy agents, provided the basis for sequential use of tamoxifen in several adjuvant chemohormonal trials started in the 1990s. The interaction of chemotherapy and tamoxifen may be quite complex in premenopausal women. Chemotherapy-induced amenorrhea is often associated with better outcomes, although controversy remains [5]. In 1992, there was substantial uncertainty as to whether tamoxifen administered with or after chemotherapy in premenopausal women was redundant or conferred benefit similar to that seen in postmenopausal women. Thus, in 1992, the National Cancer Institute of Canada—Clinical Trials Group (NCIC CTG) Breast Committee initiated Mammary (MA).12 in premenopausal women with
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Received 19 March 2009; revised 5 May 2009; accepted 6 May 2009
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Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, Alberta; 2Department of Medical Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario; Central Office, National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario; 4Department of Medical Oncology, Cross Cancer Institute, Edmonton, Alberta; 5Department of Radiation Oncology, Saskatoon Cancer Centre, Saskatoon, Saskatchewan; 6Department of Medical Oncology, London Regional Cancer Program, London, Ontario; 7Department of Surgical Oncology, Hoˆpital Du Saint-Sacrement, Quebec City, Quebec; 8Department of Medical Oncology, Juravinski Cancer Centre, Hamilton, Ontario and 9Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada 3
original article
Annals of Oncology
node-positive breast cancer, evaluating the benefit of 5 years of adjuvant tamoxifen versus placebo following completion of adjuvant chemotherapy. Participants could opt for one of three well-established chemotherapy regimens, cyclophosphamide/ methotrexate/5-fluorouracil (CMF), cyclophosphamide/ epirubicin/5-fluorouracil (CEF) as used in an NCIC CTG trial that had just been completed [6], or doxorubicin (adriamycin)/ cyclophosphamide (AC) [7].
known to be alive. Disease-free survival (DFS), the secondary efficacy end point, was calculated from randomization to the earliest date of recurrence or death or censored on the last date the patient was known to be alive. Contralateral breast cancer was considered a second primary malignancy. The worse grade of adverse event/toxicity according to the NCIC CTG Expanded Common Toxicity Criteria was recorded for each patient at randomization (baseline), during therapy with tamoxifen/placebo (acute) and after completion of therapy (not reported, except second malignancies).
patients and methods
statistical analysis
patient population
treatment plan The study was approved by local Research Ethics Boards, and patients provided written informed consent. Staging investigations included history, physical examination, complete blood count and liver function tests before chemotherapy, and chest radiograph and bone scan within 8 weeks of starting chemotherapy. Patients were required to start chemotherapy within 14 weeks of first histological diagnosis of breast cancer and to complete a course of standard adjuvant chemotherapy with six cycles of CMF or CEF [6] or four cycles of AC [7]. After stratification for type of chemotherapy (CMF versus CEF versus AC), hormone receptor status (ER and/or PgR positive versus ER and PgR negative), and nodal status (0 versus 1–3 versus 4–9 versus 10+), through the central office of NCIC CTG, women were randomized to tamoxifen/placebo on/after day 8 of cycle 6 of CMF/CEF or day 1 of cycle 4 of AC and were required to start study medication within 42 days of completing i.v. chemotherapy. Tamoxifen/placebo was provided by AstraZeneca, Missisauga, Ontario, as 20 mg tablets to be taken daily for 5 years.
follow-up After starting tamoxifen/placebo, women were seen every 3 months for 2 years, every 6 months for 3 years, and then yearly. Adverse events/toxic effects of tamoxifen/placebo were recorded. When patients stopped blinded treatments, reasons were documented, including treatment completion, recurrence, death, intercurrent illness, toxicity of treatment, refusal (for reasons other than toxicity), major protocol violation (started another hormonal therapy before progression), and others. Other hormonal therapies (including nonstudy tamoxifen) taken before progression (during or after off-protocol treatment) were also recorded.
outcome measures The primary end point was overall survival (OS), calculated from date of randomization to date of death or censored on the last day the patient was
284 | Bramwell et al.
results patient population From 1993 to 2000, 672 women were randomized: 338 to tamoxifen and 334 to placebo. Median age was 46 years (range 29–58). Other characteristics are summarized in Table 1. ER assays were done by the biochemical method in 202 (60%) of women randomized to tamoxifen and 172 (51%) on placebo. The remaining ER assays were done by immunohistochemistry (one patient on each arm had both assays). All PgR assays were done by biochemistry. Hormone receptor status was positive (ER positive and/or PgR positive) in 505 (75%) women. Eighteen patients did not meet the eligibility criteria (Appendix, Figure A1). On tamoxifen, these included one incomplete resection, six incomplete screening tests, three inappropriate chemotherapy regimens, and three not meeting high-risk criteria for node-negative disease. On placebo, five patients had incomplete screening tests. All randomized patients were included in survival analyses on an intention-to-treat basis. outcomes—OS and DFS At data cut-off for this analysis, March 2007, median follow-up was 9.7 years (range 0.2–13.1 years), and 169 women had died, 77 (23%) on tamoxifen and 92 (27.5%) on placebo (Table 2). The Kaplan–Meier curves for OS (Figure 1A) show 5-year OS
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Women with histologically confirmed breast cancer who had undergone complete or segmental mastectomy plus axillary node dissection were included. Pre-/perimenopausal status was characterized by one of the following: normal menstruation, amenorrhea <1 year, biochemical evidence of ovarian function, amenorrhea for 1–3 years in women <52 years, or hysterectomy without oophorectomy in women <56 years [criteria of the International Breast Cancer Study Group (IBCSG)]. Patients with pathological T1–4, N0–2, and M0 tumors were eligible. Initially, entry was restricted to women with node-positive disease but, from February 1995, women with high-risk node-negative tumors (tumor ‡1 cm and high histological grade or lymphovascular invasion or both) were included. Determination of levels of at least one hormone receptor [ER and/or progesterone receptor (PgR)], by biochemical (positive ‡10 fmol/mg protein) or immunohistochemical assay (as determined by the local pathologist), was required but patients with any receptor status were eligible. Patients were excluded if they had distant metastases, residual disease in the breast or axilla, other serious medical illnesses, or a previous cancer. Women considering pregnancy or using hormones were excluded. Brief exposure to tamoxifen (£2 weeks) was permitted.
The trial was designed to detect, with 80% power and a two-sided alpha of 5%, an increase in 5-year OS from 70% for women on placebo to 78% for those receiving tamoxifen [corresponding to a hazard ratio (HR) of 0.69]. This would require 242 deaths at final analysis. It was projected that this number of events would be observed by enrolling 800 patients over 5 years and following them for five additional years. The trial was activated in July 1993. Based on the recommendation of the Data Safety and Monitoring Committee (DSMC), the trial closed in April 2000 after 672 patients were randomized since, because of slow accrual, it was projected that 242 deaths would still be observed with 5 years’ additional follow-up. Two interim analyses were scheduled when one-third (80) and twothirds (160) of deaths required were observed. The DSMC recommended continuation after the first interim analysis. After reviewing results of the second interim analysis and a supplemental futility analysis, the DSMC accepted a proposal by the Trial Committee to publish these results. OS and DFS of the two treatment groups were described by Kaplan– Meier curves and compared by a log-rank test adjusting stratification factors at randomization. The Cox proportional hazards model was used to adjust the observed treatment effect for the three stratification factors and four other potential prognostic factors: age (£45 versus >45 years); Eastern Cooperative Oncology Group performance status (0 versus 1, 2); time from initial pathological diagnosis to randomization (£6 versus >6 months); and pathological T stage (£2 versus >2 cm). The chi-square test was used to compare rates of adverse events/toxicity between treatment groups. All statistical tests were two sided.
original article
Annals of Oncology
For DFS, there were 226 recurrences or deaths without recurrence, 105 (31%) on tamoxifen and 121 (36%) on placebo (Table 2). The Kaplan–Meier curves for DFS (Figure 1B) show 5year DFS rates of 78.2% on tamoxifen and 71.3% on placebo. The HR from the stratified Cox proportional hazards model was 0.77 (95% CI 0.59–1.01; P = 0.056). Table 3 shows that as for OS, there was no evidence for a greater effect of tamoxifen on DFS in the hormone receptor-positive or ER-positive subgroups (P values of interaction tests 0.87 and 0.26, respectively).
Table 1. Patient characteristics according to treatment arms
protocol treatment Ten patients on tamoxifen and seven on placebo never started protocol treatment. Among them, one on tamoxifen and zero on placebo were ineligible. All patients were off-protocol treatment at time of data cut-off. Of women starting treatment, 103 (31%) on tamoxifen and 70 (21%) on placebo stopped early because of toxicity, refusal, protocol violation, and other causes (Table 4). Overall, 29% on tamoxifen and 27% on placebo received £2 years of protocol treatment. Forty-one (12.5%) on tamoxifen and 32 (10%) on placebo received other hormones before recurrence, which included progestogens for menopausal symptoms, tamoxifen extended beyond 5 years, and aromatase inhibitors (Table 4). Among them, 17 on tamoxifen and 22 on placebo started off-label tamoxifen before the scheduled end of blinded treatment.
Characteristic Receptor status ER and/or PgR positive ER and PgR negative ER negative and PgR unknown ER positive ER negative PgR positive PgR negative PgR unknown Nodal status Node negative 1–3 nodes 4–9 nodes 10+ nodes Adjuvant chemotherapy CEF CMF AC Age £29 30–39 40–49 ‡50 Stage (pathological) I II III Pathological T stage 1 2 3/4 ECOG status 0 1 2 Menstrual status (at randomization) Regular menses Irregular menses No menses >3 months Previous hysterectomy No data
Tamoxifen n %
Placebo n %
Total N %
252 50 36
74 15 11
253 26 55
76 8 16
505 75 76 11 91 14
223 115 132 60 146
66 34 39 18 43
231 103 119 41 174
69 31 36 12 52
454 218 251 101 320
84 190 55 9
25 56 16 3
83 187 53 11
25 56 16 3
167 25 377 56 108 16 20 3
73 153 112
22 45 33
73 151 110
22 45 33
146 22 304 45 222 33
68 32 37 15 48
1 64 210 63
0 19 62 19
2 66 210 56
0 20 63 17
3 0 130 19 420 63 119 18
33 284 21
10 84 6
37 278 19
11 83 6
70 10 562 84 40 6
140 179 19
41 53 6
149 165 20
45 49 6
289 43 344 51 39 6
234 100 4
69 30 1
206 125 3
62 37 1
440 65 225 34 7 1
85 36 129 17 71
25 11 38 5 21
93 39 121 20 61
28 12 36 6 18
178 75 250 37 132
ER, estrogen receptor; PgR, progesterone receptor; CEF, cyclophosphamide/epirubicin/fluorouracil; CMF, cyclophosphamide/ methotrexate/5-fluorouracil; AC, doxorubicin(adriamycin)/ cyclophosphamide; ECOG, Eastern Cooperative Oncology Group.
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26 11 37 6 20
adverse events/toxicity Toxicity was evaluated in 328 patients on tamoxifen and 327 on placebo who started protocol treatment (Appendix, Figure A1). Table 2. Outcome events—deaths and recurrences by treatment arm Tamoxifen n Patients OS—total deaths Breast cancer Other malignancy Othera DFS—total events Recurrences Locoregional only Breast Chest wall Regional nodes Distant only Multiple sites Boneb Liver Lung Brain Ascites/effusions Other Death without recurrence
338 77 72 2 3 105 101 17 11 2 4 51 33 59 45 40 24 38 30 4
% 23
31 30 5
15 10
1
Placebo n 334 92 86 4 2 121 116 14 10 1 3 57 45 69 54 53 27 47 34 5
% 28
36 35 4
17 13
1
a
Tamoxifen: nonprotocol treatment complication (1), intracranial bleed (1), unknown, but extensive metastases (1); placebo: motor vehicle accident (1), suspected suicide (1). b Single patient can have multiple sites of recurrence. OS, overall survival; DFS, disease-free survival.
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rates of 86.6% on tamoxifen and 82.1% on placebo. The HR from the stratified Cox proportional hazards model was 0.78 [95% confidence interval (CI) 0.57–1.06; P = 0.12]. The effect of tamoxifen was explored in subgroups defined by overall hormone receptor and ER receptor-only status (Table 3). There was no evidence of greater efficacy for tamoxifen in the hormone receptor-positive or ER receptor-positive subgroups (P values of interaction tests 0.71 and 0.14, respectively).
original article
Annals of Oncology
discussion
Figure 1. (A) Kaplan–Meier curves for overall survival, tamoxifen versus placebo; (B) Kaplan–Meier curves for disease-free survival, tamoxifen versus placebo.
In this placebo-controlled study, adjuvant tamoxifen following chemotherapy produced improved DFS (HR 0.77; P = 0.056) and a trend for improved OS (HR 0.78; P = 0.12) in premenopausal women with EBC. Although exploratory subgroup analysis indicated a trend for greater benefit in women with ER-negative tumors, this was not statistically significant. Such a finding has no biological rationale and is not in agreement with results of other similar studies [8–10]. A number of factors delayed analysis of this trial to a time when use of adjuvant tamoxifen has become standard practice after adjuvant chemotherapy in premenopausal women with receptor-positive tumors. In the late 1990s, slow accrual probably reflected an increasing conviction among physicians and patients that tamoxifen was beneficial in this setting, despite limited data actually available at that time [11]. The study was closed with a reduced sample size because of slow
Table 3. Effect of tamoxifen on OS and DFS according to hormone receptor subgroups Tamoxifen Total patients OS Receptor status ER and/or PgR positive ER and PgR negative ER negative, PgR unknown ER status Positive Negative DFS Receptor status ER and/or PgR positive ER and PgR negative ER negative, PgR unknown ER status Positive Negative
% Surviving 5 years
Placebo Total patients
% Surviving 5 years
HR (95% CI)
252 50 36
90 76 78
253 26 55
85 73 72
0.83 (0.58–1.18) 0.78 (0.34–1.81) 0.67 (0.29–1.56)
223 115
90 81
231 103
86 72
0.94 (0.65–1.38) 0.61 (0.37–1.01)
251 50 36
80 70 78
253 26 55
73 69 65
0.82 (0.61–1.11) 0.83 (0.38–1.82) 0.65 (0.30–1.43)
222 115
79 77
231 103
75 64
0.90 (0.66–1.24) 0.65 (0.41–1.03)
OS, overall survival; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; PgR, progesterone receptor.
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At baseline, 54% and 50% of women subsequently randomized to tamoxifen and placebo, respectively, were complaining of hot flashes. Similar numbers in each arm, 129 (38%) on tamoxifen and 121 (36%) on placebo, had ceased menstruation for at least 3 months, and a further 36 (11%) on tamoxifen and 39 (12%) on placebo were having irregular periods (Table 1). Large numbers of grade 1/2 acute toxic effects were reported but were similarly distributed across the arms. For grade 3/4 (Appendix, Table A1) toxic effects, the only important difference was in frequency of severe hot flashes, which were significantly worse on tamoxifen (tamoxifen 23% versus placebo 14%; P = 0.005). Twenty-one (6%) patients on tamoxifen and 33 (10%) on placebo developed 56 second malignancies. There were fewer contralateral breast cancers (14 versus 18) and fewer other malignancies (7 versus 17; P = 0.07) in the tamoxifen arm. The only two cases of endometrial cancer were on placebo.
original article
Annals of Oncology
Table 4. Compliance with study medication Placebo n
%
338
100
334
100
175 50 1 9 29 44 13 17 328
52 15 0 3 8 13 4 5 100
174 78 1 11 15 35 12 8 327
52 23 0 3 5 11 4 2 100
64 33 19 23 189 7
19 10 6 7 58 2
45 41 31 21 189 2
14 13 9 6 58 1
10
2 0 0 30
9
0 1 6 34
17 12 1 0 4
20 1 0 3 2
0 11 1
5 2 0
a
Included development of contralateral breast cancer. Ineligible, noncompliant, stopped early/unblinded in error, physician advice, desire for pregnancy, left the country. c A patient may have received more than one hormonal agent. b
accrual after recruitment of 672 women (planned accrual 800) based on recalculation of the statistical assumptions, as outlined in the ‘Patients and Methods’ section. Our primary end point was OS, but over the time span of the trial, mortality was much lower than anticipated, probably because of increasing efficacy of adjuvant therapies and better salvage therapies for metastatic disease. The recent declining mortality for women with EBC has been well documented across many countries [12]. Several studies of similar design (evaluating tamoxifen given after adjuvant chemotherapy in premenopausal women with EBC) have demonstrated improvements in DFS, but are not
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Total off treatment Reasons Treatment completed Recurrence/progression Death Intercurrent illnessa Toxicity treatment Refusal Protocol violation Otherb Number treated patients Duration of study medication (months) 0–12 13–24 25–36 37–48 49–60 Other hormones before progression and during protocol treatmentc Tamoxifen Letrozole Progestogen Other hormones before progression and after protocol treatmentc Not completed 5 years of blinded treatment Tamoxifen Letrozole Anastrozole Exemestane Progestogen Completed 5 years of blinded treatment Tamoxifen Letrozole Exemestane
Tamoxifen n %
definitive with respect to OS [8–10]. Our study is the remaining unpublished randomized trial directly addressing this question. A future individual patient data meta-analysis may be more informative concerning the effects of tamoxifen on OS in this population. The study most comparable to ours was conducted by the IBCSG (13.93), 1993–1999, and recruited premenopausal nodepositive women [8]. All received chemotherapy followed by randomization to tamoxifen for 5 years or no endocrine therapy. Of 1246 assessable patients, 735 (59%) had ER-positive tumors, and patients receiving tamoxifen versus control had improved DFS at 5 years (75% versus 62%; HR 0.59; P = 0.0001), although no benefit was seen in the ER-negative cohort. There were no significant differences in OS in ER-positive (HR 0.86; P = 0.36) or ER-negative subgroups (HR 0.92; P = 0.63). Intergroup protocol INT-0102 [9], 1989–1993, compared 5 years of tamoxifen with no endocrine therapy in 1690 women with high-risk node-negative breast cancer (56% premenopausal) who had completed adjuvant chemotherapy. At 10 years, improved DFS (HR 1.32; P = 0.003) and OS (HR 1.26; P = 0.03) were seen in the ER-positive subgroup, but not overall. Subgroup analysis was not carried out according to menopausal status. In European Organisation for Research and Treatment of Cancer (EORTC) study 10901 [10], 1863 women recruited 1991–1999, after chemotherapy, were randomized between tamoxifen 20–30 mg daily for 3 years or no endocrine therapy. Analysis was based on 1724 patients, 73% of whom were pre-/ perimenopausal. Five-year DFS figures were 67% versus 63%, favoring tamoxifen (HR 0.84; P = 0.035). Benefit was greater in the ER-positive subgroup, but menopausal status did not influence effects of treatment. In a North American setting, adjuvant chemotherapy remains the standard of care for premenopausal women with high-risk node-negative or node-positive EBC. For women with endocrine-responsive (hormone receptor positive) tumors, chemotherapy is usually followed by 5 years of tamoxifen. However, several European studies have shown that ovarian function suppression with or without tamoxifen can be as effective as standard CMF chemotherapy [13–15]. IBCSG is leading an international collaboration exploring ovarian function suppression with or without adjuvant chemotherapy in premenopausal women with EBC, through two ongoing randomized trials (IBCSG 24.02 Suppression of Ovarian Function, IBCSG 25.02 Tamoxifen and Exemestane Trial) [16]. The placebo-controlled design of our study allowed us to collect detailed comparative data on compliance, and we found that 31% on tamoxifen and 21% on placebo-stopped study medication prematurely for reasons other than recurrence, death, or intercurrent illness. The greatest attrition occurred in the first 24 months. Although data from EBCTCG [1, 17] showed benefit for durations of adjuvant tamoxifen as short as 1 year, results were better with longer therapy and currently, at least 5 years of therapy is regarded as optimal. We know that 17 stopping tamoxifen and 22 stopping placebo went on to receive open-label tamoxifen, but this may be an underestimate given its wide availability. As few patients received aromatase inhibitors, it is unlikely that their use affected efficacy outcomes.
original article
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To date, second malignancy rates are low and do not differ significantly between the arms. The only two cases of endometrial cancer occurred on placebo, and it is probable that women entering the menopause are less susceptible to the carcinogenic effects of tamoxifen on the endometrium [29]. A delayed effect is still possible, although all women have been off therapy for 1–8 years. In conclusion, in MA.12, DFS at 5 years was marginally improved for premenopausal women receiving 5 years of tamoxifen after adjuvant chemotherapy for EBC. However, poor compliance with therapy is likely to have influenced the efficacy of treatment in this trial and other similar studies. Some of the compliance issues clearly related to the physical and emotional consequences of early menopause induced by adjuvant chemotherapy, but there were other contributory factors (Table 4). These findings have implications for the use of oral anticancer medications in many settings [30].
funding AstraZeneca, through the National Cancer Institute of Canada Clinical Trials Group; Canadian Cancer Society, through the National Cancer Institute of Canada (# 4448).
acknowledgement This paper was presented at American Society Clinical Oncology meeting 2007 and San Antonio Breast Cancer Symposium 2007.
references 1. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31 000 recurrences and 24 000 deaths among 75 000 women. Lancet 1992; 339: 71–85. 2. Albain KS, Green SJ, Ravdin PM et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 2002; 21: 37a (Abstr 143). 3. Osborne CK. Effects of estrogens and antiestrogens on cell proliferation: implications for the treatment of breast cancer. Cancer Treat Res 1988; 39: 111–129. 4. Goldenberg GJ, Froese EK. Antagonism of the cytocidal activity and uptake of melphalan by tamoxifen in human breast cancer cells in vitro. Biochem Pharmacol 1985; 34: 763–770. 5. Walshe JM, Neelima D, Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 2006; 24: 5769–5779. 6. Levine MN, Bramwell VH, Pritchard KI et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil in premenopausal women with node positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1998; 16: 2651–2658. 7. Fisher B, Anderson S, Tan-Chiu E et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 2001; 19: 931–942. 8. International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 2006; 24: 1332–1341. 9. Hutchins LF, Green SJ, Ravdin PM et al. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil with and without tamoxifen for
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The influence of compliance issues on the main efficacy outcomes will have been complex although a dilution of the potential beneficial effects of tamoxifen seems likely. None of the other comparable studies was placebo controlled, and data on other hormonal therapies used by women in control arms were not reported [8–10]. In INT-0102 [9], 57% of women completed ‡4.5 years of tamoxifen, with 8% stopping due to toxicity and 7% refusing therapy. In IBCSG-93 [8], 8% of women did not start tamoxifen and 33% discontinued drug prematurely. In EORTC 10901 [10], 4.4% stopped tamoxifen due to toxicity. In this study, a shorter planned duration of tamoxifen (3 years) may account for the lower dropout rate, but methodology for documenting compliance was not reported. Early discontinuation of hormonal therapy has also been reported in aromatase inhibitor studies. In ATAC, 22%–26% across the three arms withdrew from therapy [18]. A lower proportion of patients in Intergroup Exemestane Study, 13%–15%, discontinued therapy prematurely after a median of 36 months [19]. In MA.17, 19%–20% of women discontinued treatment early [20]. Compliance data were not reported for BIG 1–98 [21]. In a practice setting, problems with adherence to aromatase inhibitor therapy have also been documented [22]. Poor compliance with adjuvant tamoxifen has been described in clinical practice. Partridge et al. [23], documenting filled prescriptions for adjuvant tamoxifen among 2378 women through New Jersey’s Pharmaceutical prescription program, found that 23% of patients missed taking tamoxifen on >20% of days studied, although 87% filled prescriptions in the first year. Overall adherence was 50% by year 4. Also using prescription refill data from a national prescribing database, Barron et al. [24] found that 22% of 2816 women stopped tamoxifen within 1 year, increasing to 35% at 3.5 years. Data from another community-based study of 2080 women demonstrated a correlation between poor adherence to adjuvant tamoxifen and increased risk of death from breast cancer [25]. The gaps between evidence-based recommendations for adjuvant hormonal therapy and clinical practice were the subject of a recent editorial [26]. Genetic variation in cytochrome P-450 2D6 affecting metabolism of tamoxifen may account for different degrees of toxicity and thus compliance [27]. In MA.12, amenorrhea rates were close to 50% after chemotherapy before randomization to tamoxifen/placebo, but were similar between the arms, and this is unlikely to have influenced the efficacy of treatment. Many ‘toxic effects’ recorded in our study, for both tamoxifen and placebo, probably were related to chemotherapy-induced menopause [28] and/or prolonged chemotherapy-related side-effects, particularly in the first year. This may account for higher dropout rates in studies including high proportions of premenopausal women treated with adjuvant chemotherapy, compared with aromatase inhibitor trials in which all women were postmenopausal, regardless of whether they received chemotherapy. Toxic effects clearly worse on tamoxifen included vaginal discharge/fibrosis and hot flashes, as documented in other studies. Our finding that mood changes were more frequent on placebo indicates that these are not specific side-effects of tamoxifen, but have other causes such as premature menopause, the emotional toll of the disease, and effects of multiple treatments.
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high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 2005; 23: 8313–8321. 10. Morales L, Canney P, Dyczka J et al. Postoperative adjuvant chemotherapy followed by adjuvant tamoxifen versus nil for patients with operable breast cancer: a randomized phase III trial of the European Organisation for Research and Treatment of Cancer Breast Group. Eur J Cancer 2007; 43: 331–340. 11. Bramwell VHC, Pritchard KI. Tamoxifen added to adjuvant chemotherapy in premenopausal women with early breast cancer: is it standard practice or still a subject for study? Eur J Cancer 1999; 35: 1625–1627. 12. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005; 365: 1687–1717.
14. Jonat W, Kaufmann M, Sauerbrei W et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002; 20: 4628–4635. 15. Jakesz R, Hausmaninger H, Kubista E et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002; 20: 4621–4627. 16. Regan MM, Pagani O, Walley B et al. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy? Ann Oncol 2008; 19: 1213–1215.
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appendix
Figure A1. Consort diagram.
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13. Boccardo F, Rubagotti A, Amoroso D et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. J Clin Oncol 2000; 18: 2718–2727.
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adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 2002; 359: 2131–2139. Coombes RC, Hall E, Gibson LJ et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women wit primary breast cancer. N Engl J Med 2004; 350: 1081–1092. Goss PE, Ingle JN, Martino S et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005; 97: 1262–1271. The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2747–2757. Partridge AH, LaFountain A, Mayer E et al. Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol 2008; 26: 556–562. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 2003; 15: 602–606. Barron TI, Connolly RM, Bennett K et al. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer 2007; 109: 832–839. McCowan D, Shearer J, Donnan PT et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008; 99: 1763–1768. Kahn KL. Moving research from bench to bedside to community: there is still more to do. J Clin Oncol 2008; 26: 523–526. Rae JM, Sikora MJ, Henry NL et al. Cytochrome p450 2D6 activity predicts adherence to tamoxifen therapy. Breast Cancer Res Treat 2007; 106: S21 (Abstr 77). Tchen N, Juffs HG, Downie FP et al. Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol 2003; 21: 4175–4183. Fisher B, Costantino JP, Redmond CK et al. Endometrial cancer in tamoxifentreated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86: 527–537. Partridge AH. Non-adherence to endocrine therapy for breast cancer. Ann Oncol 2006; 17: 183–184.
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Table A1. Numbers of acute adverse events/toxic effects (>10% incidence either arm) Adverse event
4
Total (%)
%R
Placebo (327 patients) 1 2 3
4
Total (%)
%R
82 69 79
30 10 3
3 5 0
0 3 0
115 (35) 87 (27) 82 (25)
0 0 0
74 44 45
20 14 2
1 6 0
0 0 0
95 (29) 64 (20) 47 (14)
1 0 0
44
11
0
0
55 (17)
6
61
9
0
0
70 (21)
7
16 61
205 134
0 75
0 0
221 (67) 270 (82)
34 78
26 87
198 131
0 47
0 0
224 (69) 265 (81)
37 75
60 125 40
13 24 13
4 1 3
0 0 0
77 (23) 150 (46) 56 (17)
4 19 4
59 136 43
33 27 17
4 3 3
0 0 0
96 (29) 166 (51) 63 (19)
4 23 2
45 21
8 6
1 0
0 0
54 (16) 27 (8)
7 1
46 29
8 9
1 3
0 0
55 (17) 41 (13)
8 2
66
22
0
0
88 (27)
21
55
9
2
0
66 (20)
15
28 44
1 8
0 2
0 0
29 (9) 54 (16)
0 1
90 32
2 4
0 1
0 0
92 (28) 37 (11)
0 0
11
13
1
0
25 (8)
1
16
17
0
0
33 (10)
1
15 20 60 39 37
20 11 40 11 5
3 0 6 3 0
0 0 0 0 0
(12) (9) (32) (16) (13)
4 3 17 2 2
27 24 80 55 48
20 13 46 16 4
1 3 7 1 1
0 0 1 0 0
20
11
2
0
33 (10)
1
29
15
3
22
3
0
0
25 (8)
0
22
8
17 14 32
6 1 11
2 0 1
0 0 0
25 (8) 15 (5) 44 (13)
1 1 3
33 29 31
10 3 14
38 31 106 53 42
48 40 134 72 53
(15) (12) (41) (22) (16)
4 4 21 2 2
0
47 (14)
3
2
0
32 (10)
0
0 0 1
0 0 0
43 (13) 32 (10) 46 (14)
2 1 3
%R = considered by investigator to be ‘possibly’, ‘probably’, or ‘definitely’ related to protocol treatment. WBC, white blood cell; Hb, hemoglobin; ALP, alkaline phosphatase; AST, aspartate aminotransferase.
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Blood WBC Neutrophils Hb Cardiovascular Edema Endocrine Amenorrhea Hot flashes Influenza-like symptoms Arthralgia Lethargy Myalgia Gastrointestinal Nausea Abdominal pain Genitourinary Vaginitis/fibrosis Hepatic ALP AST Infection Infection Neurological Headache Insomnia Mood Pain Sensory Osseous Bone pain Pulmonary Cough Skin Alopecia Skin changes Rash/itch
Tamoxifen (328 patients) 1 2 3